Compounds

ABSTRACT

This invention relates to the novel pyrazole compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable diluent or carrier. 
     This invention also relates to a method of inhibiting cytokines by a compound of Formula (I) and the treatment of cytokine mediated diseases, in mammals, by administration of said compound.

FIELD OF THE INVENTION

This invention relates to a novel group of pyrimidine compounds,processes for the preparation thereof, the use thereof in treatingcytokine mediated diseases and pharmaceutical compositions for use insuch therapy.

BACKGROUND OF THE INVENTION

Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biologicalsubstances produced by a variety of cells, such as monocytes ormacrophages. IL-1 has been demonstrated to mediate a variety ofbiological activities thought to be important in immunoregulation andother physiological conditions such as inflammation [See, e.g.,Dinarello et at., Rev. Infect. Disease, 6, 51 (1984)]. The myriad ofknown biological activities of IL-1 include the activation of T helpercells, induction of fever, stimulation of prostaglandin or collagenaseproduction, neutrophil chemotaxis, induction of acute phase proteins andthe suppression of plasma iron levels.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, endotoxemia and/ortoxic shock syndrome, other acute or chronic inflammatory disease statessuch as the inflammatory reaction induced by endotoxin or inflammatorybowel disease; tuberculosis, atherosclerosis, muscle degeneration,cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis,gout, traumatic arthritis, rubella arthritis, and acute synovitis.Recent evidence also links IL-1 activity to diabetes and pancreatic βcells.

Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985), reviews thebiological activities which have been attributed to IL-1. It should benoted that some of these effects have been described by others asindirect effects of IL-1.

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions; sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusioninjury, graft vs. host reaction, allograft rejections, fever andmyalgias due to infection, such as influenza, cachexia secondary toinfection or malignancy, cachexia, secondary to acquired immunedeficiency syndrome (ADS), AIDS, ARC (AIDS related complex), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis,or pyresis.

AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least three types or strains of HIVhave been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence ofHIV infection, T-cell mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HIV entry into the T lymphocyte requires T lymphocyteactivation. Other viruses, such as HIV-1, HIV-2 infect T lymphocytesafter T Cell activation and such virus protein expression and/orreplication is mediated or maintained by such T cell activation. Once anactivated T lymphocyte is infected with HIV, the T lymphocyte mustcontinue to be maintained in an activated state to permit HIV geneexpression and/or HIV replication. Monokines, specifically TNF, areimplicated in activated T-cell mediated HIV protein expression and/orvirus replication by playing a role in maintaining T lymphocyteactivation. Therefore, interference with monokine activity such as byinhibition of monokine production, notably TNF, in an HIV-infectedindividual aids in limiting the maintenance of T cell activation,thereby reducing the progression of HIV infectivity to previouslyuninfected cells which results in a slowing or elimination of theprogression of immune dysfunction caused by HIV infection. Monocytes,macrophages, and related cells, such as kupffer and glial cells, havealso been implicated in maintenance of the HIV infection. These cells,like T-cells, are targets for viral replication and the level of viralreplication is dependent upon the activation state of the cells. [SeeRosenberg et al., The Immunopathogenesis of HIV Infection, Advances inImmunology, Vol. 57, (1989)]. Monokines, such as TNF, have been shown toactivate HIV replication in monocytes and/or macrophages [See Poli, etal., Proc. Natl. Acad. Sci., 87:782-784 (1990)], therefore, inhibitionof monokine production or activity aids in limiting HIV progression asstated above for T-cells.

TNF has also been implicated in various roles with other viralinfections, such as the cytomegalia virus (CMV), influenza virus, andthe herpes virus for similar reasons as those noted.

Interleukin-8 (IL-8) is a chemotactic factor first identified andcharacterized in 1987. Il-8 is produced by several cell types includingmononuclear cells, fibroblasts, endothelial cells, and kertainocytes.Its production from endothelidl cells is induced by IL-1, TNF, orlipopolysachharide (LPS). Human IL-8 has been shown to act on Mouse,Guinea Pig, Rat, and Rabbit Neutrophils. Many different names have beenapplied to IL-8, such as neutrophil attractant/activation protein-1(NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF),neutophil activating factor (NAF), and T-cell lymphocyte chemotacticfactor.

Il-8 stimulates a number of functions in vitro. It has been shown tohave chemoattractant properties for neutophils, T-lymphocutes, andbasophils. In addition it induces histamine release from basophils fromboth normal and atopic individuals as well as lysozomal enzyme releaseand respiratory burst from neutrophils. Il-8 has also been shown toincrease the surface expression of Mac-1 (CD11b/CD18) on neutrophilswithout de novo protein synthesis, this may contribute to increasedadhesion of the neutrophils to vascular endothelial cells. Many diseasesare characterized by massive neutrophil infiltration. Conditionsassociated with an increased in IL-8 production (which is responsiblefor chemotaxis of neutrophils into the inflammatory site) would benefitby compounds which are suppressive of IL-8 production.

IL-1 and TNF affect a wide variety of cells and tissues and thesecytokines as well as other leukocyte derived cytokines are important andcritical inflammatory mediators of a wide variety of disease states andconditions. The inhibition of these cytokines is of benefit incontrolling, reducing and alleviating many of these disease states.

There remains a need for treatment, in this field, for compounds whichare cytokine suppressive anti-inflammatory drugs (hereinafter CSAID's),i.e. compounds which are capable of inhibiting cytokines, such as IL-1,IL-6, IL-8 and TNF.

SUMMARY OF THE INVENTION

This invention relates to the novel compounds of Formula (I) andpharmaceutical compositions comprising a compound of Formula (I) and apharmaceutically acceptable diluent or carrier.

This invention also relates to a method of inhibiting cytokines and thetreatment of a cytokine mediated disease, in a mammal in need thereof,which comprises administering to said mammal an effective amount of acompound of Formula (I).

This invention more specifically relates to a method of inhibiting theproduction of IL-1 in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I).

This invention more specifically relates to a method of inhibiting theproduction of IL-8 in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I).

This invention more specifically relates to a method of inhibiting theproduction of TNF in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I).

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of this invention are represented by the structurehaving the formula (I): ##STR1## wherein one of R₁ and R₂ is selectedfrom is 4-pyridyl, 4-pyrimidinyl, 4-quinolyl, 4-isoquinolinyl,4-quinazolinyl, which is optionally substituted with one or twosubstituents each of which is independently selected from C₁₋₄ alkyl,halo, C₁₋₄ alkoxy, C₁₋₄ alkylthio, CH₂ OR₁₆, NH₂, mono- or di-C₁₋₆-alkylamino or N-heterocyclyl ring which ring has from 5 to 7 membersand optionally contains an additional heteroatom selected from oxygen,sulfur or NR₂₂ ; and

the other of R₁ and R₂ is selected from an optionally substituted arylor optionally substituted heteroaryl group, provided that both R₁ and R₂are not the same heteroaryl group; wherein when one R₁ and R₂ is anoptionally substituted aryl ring, the ring is substituted by one or twosubstituents, each of which is independently selected, and which, for a4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl substituent, is halo, cyano,--C(Z)NR₁₃ R₁₄, --C(Z)OR₂₃, --(CR₁₀ R₂₀)_(n) COR₃₆, --SR₅, --S(O)R₅,--OR₃₆, halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, --ZC(Z)R₃₆, --NR₁₀C(Z)R₂₃, or --(CR₁₀ R₂₀)_(n) NR₁₀ R₂₀ and which, for other positions ofsubstitution, is halo, cyano, --C(Z)NR₇ R₁₇, --C(Z)OR₈, --(CR₁₀ R₂₀)_(n)COR₈, --S(O)_(m) R₈, --OR₈, halo-substituted-C₁₋₄ alkyl, --C₁₋₄ alkyl,--(CR₁₀ R₂₀)_(n) NR₁₀ C(Z)R₈, --NHS(O)_(m) R₆, --NHS(O)_(m) NR₇ R₁₇,--NR₆ S(O)_(m) R₆, --NR₆ S(O)_(m') NR₇ R₁₇ wherein m' is 1 or 2,--ZC(Z)R₈ or --(CR₁₀ R₂₀)_(n) NR₇ R₁₇ ; and when one of R₁ and R₂ is anoptionally substituted heteroaryl group, the substituent groups includeone or two substituents each of which is independently selected fromC₁₋₄ alkyl, halo, C₁₋₄ alkoxy, C₁₋₄ alkylthio, NR₁₀ R₂₀, or anN-heterocyclyl ring which ring has from 5 to 7 members and optionallycontains an additional heteroatom selected from oxygen, sulfur or NR₁₂ ;

n is 0 or an integer of 1 or 2;

n' is 0 or an integer having a value of 1 to 10;

n' is an integer having a value of 1 to 10

m is 0 or an integer of 1 or 2;

m' is an integer of 1 or 2;

m' is an integer having a value of 1 to 10;

R₃ is Q-(Y₁)_(t) ;

Q is an aryl or heteroaryl group;

t is an integer having a value of 1 to 3;

R₄ is hydrogen, NR₁₆ R₂₆, NR₁₀ C(Z)R₁₁, NR₁₀ C(Z)NR₁₆ R₂₆, NR₁₀C(═NR₁₉)NR₁₆ R₂₆, or NR₁₀ C(Z)OR₁₀ ;

R₆ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₁₀ alkyl, heterocyclyl,heterocyclylC₁₋₁₀ alkyl, heterocyclyl-C₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl;

R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR₇ R₁₇,excluding the moieties --SR₅ being --SNR₇ R₁₇ and --SOR₅ being --SOH;

R₁₆ and R₂₆ are independently hydrogen, or C₁₋₄ alkyl or R₁₆ and R₂₆together with the nitrogen to which they are attached form aheterocyclic or heteroaryl ring of 5-7 members optionally conatining anadditional heteroatom selected from oxygen, sulfur or NR₂₂ ;

Y₁ is independently selected from hydrogen, C₁₋₅ alkyl, halo-substitutedC₁₋₅ alkyl, halogen, or --(CR₁₀ R₂₀)_(n) Y₂ ;

Y₂ is hydrogen, halogen, --OR₈, --NO₂, --S(O)_(m') R₁₁, --SR₈,--S(O)_(m') OR₈, --S(O)_(m) NR₈ R₉, --NR₈ R₉, --O(CR₁₀ R₂₀)_(n) NR₈ R₉,--C(O)R₈, --CO₂ R₈, --CO₂ (CR₁₀ R₂₀)_(m") CONR₈ R₉, --ZC(O)R₈, --CN,--C(Z)NR₈ R₉, --NR₁₀ C(Z)R₈, --C(Z)NR₈ OR₉, --NR₁₀ C(Z)NR₈ R₉, --NR₁₀S(O)_(m) R₁₁, --N(OR₂₁)C(Z)NR₈ R₉, --N(OR₂₁)C(Z)R₈, --C(═NOR₂₁)R₈,--NR₁₀ C(═NR₁₅)SR₁₁, --NR₁₀ C(═NR₁₅)NR₈ R₉, --NR₁₀ C(═CR₁₄ R₂₄)SR₁₁,--NR₁₀ C(═CR₁₄ R₂₄)NR₈ R₉, --NR₁₀ C(O)C(O)NR₈ R₉, --NR₁₀ C(O)C(O)OR₁₀,--C(═NR₁₃)NR₈ R₉, --C(═NOR₁₃)NR₈ R₉, --C(═NR₁₃)ZR₁₁, --OC(Z)NR₈ R₉,--NR₁₀ S(O)_(m) CF₃, --NR₁₀ C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadizaol-3-yl or4-(R₁₂)-5-(R₁₈ R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl;

R₇ and R₁₇ is each independently selected from hydrogen or C₁₋₄ alkyl orR₇ and R₁₇ together with the nitrogen to which they are attached form aheterocyclic ring of 5 to 7 members which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR₂₂ ;

R₈ is hydrogen, C₁₋₁₀ alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl;

R₉ is hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl or R₈ and R₉ may together with the nitrogen to whichthey are attached form a heterocyclic or heteroaryl ring of 5 to 7members which ring optionally contains an additional heteroatom selectedfrom oxygen, sulfur or NR₁₂ ;

R₁₀ and R₂₀ is each independently selected from hydrogen or C₁₋₄ alkyl;R₁₁ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, heterocyclic, heterocyclicC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroaryl C₁₋₁₀alkyl;

R₁₂ is hydrogen, --C(Z)R₁₃ or optionally substituted C₁₋₄ alkyl,optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl;

R₁₃ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclylC₁₋₁₀ alkyl aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl;

R₁₄ and R₂₄ is each independently selected from hydrogen, alkyl, nitroor cyano;

R₁₅ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl;

R₁₆ and R₂₆ is each independently selected from hydrogen or optionallysubstituted C₁₋₄ alkyl, optionally substituted aryl or optionallysubstituted aryl-C₁₋₄ alkyl, or together with the nitrogen which theyare attached form a heterocyclic ring of 5 to 7 members which tingoptionally contains an additional heteroatom selected from oxygen,sulfur or NR₁₂ ;

R₂₁ is hydrogen, a pharmaceutically acceptable cation, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylalkyl,heterocyclyl, aroyl, or C₁₋₁₀ alkanoyl;

R₂₂ is R₁₀ or C(Z)-C₁₋₄ alkyl;

R₂₃ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₅ cycloalkyl;

R₃₆ is hydrogen or R₂₃ ;

or a pharmaceutically acceptable salt thereof.

Suitable hetereoaryl moieties for R₁ and R₂ are 4-pyridyl, pyrimidinyl,quinolyl, or isoquinolinyl, all of which may be optionally substituted.Preferably the heteroaryl group is a 4-pyridyl, 4-pyrimidinyl,4-quinolyl, or 6-isoquinolinyl group, of which the 4-pyridyl,4-pyrimidinyl and 4-quinolyl is more preferred and especially preferredis the 4-pyridyl or 4-pyrimidinyl moiety.

Suitable substituent groups for the heteroaryl moieties, R₁ and R₂,include one or two substituents each of which are independently selectedfrom C₁₋₄ alkyl, halo, C₁₋₄ alkoxy, C₁₋₄ alkylthio, NR₁₀ R₂₀ or anN-heterocyclyl ring which ring has from 5 to 7 members and optionallycontains an additional heteroatom selected from oxygen, sulfur or NR₂₂.

Preferred substituents for the heteroaryl moieties R₁ is C₁₋₄ alkyl, andNR₁₀ R₂₀. Preferably the C₁₋₄ alkyl is methyl, and for NR₁₀ R₂₀ both R₁₀and R₂₀ are hydrogen, if alkyl it is of 1-4 carbons in length orshorter, such as 1 to 2 carbons, preferably methyl. Preferably the4-pyridyl group is substituted in the 2-position and the 4-pyrimidinylgroup is substituted at the 2- or 4-position.

For the purposes herein the "core" 4-pyrimidinyl moiety for R₁ or R₂ isreferred to as the formula: ##STR2##

Suitable aryl groups for the other of R₁ or R₂ include optionallysubstituted phenyl, naphth-1-yl or naphth-2-yl. The aryl ring may beoptionally substituted by one or two substituents, each of which isindependently selected, and which, for a 4-phenyl, 4-naphth-1-yl or5-naphth-2-yl substituent, is halo, cyano, --C(Z)NR₁₃ R₁₄, --C(Z)OR₂₃,--(CR₁₀ R₂₀)_(n) COR₃₆, --SR₅, --SOR₅, --OR₃₆, halo-substituted-C₁₋₄alkyl, C₁₋₄ alkyl, --ZC(Z)R₃₆, --NR₁₀ C(Z)R₂₃, or --(CR₁₀ R₂₀)_(n) NR₁₀R₂₀ and which, for other positions of substitution, is halo, cyano,--C(Z)NR₇ R₁₇, --C(Z)OR₈, --(CR₁₀ R₂₀)_(n) COR₈, --S(O)_(m) R₈, --OR₈,halo-substituted-C₁₋₄ alkyl, --C₁₋₄ alkyl, --(CR₁₀ R₂₀)_(n) NR₁₀ C(Z)R₈,--NHS(O)_(m) R₆, --NHS(O)_(m) NR₇ R₁₇, --NR₆ S(O)_(m) R₆, --NR₇S(O)_(m') NR₇ R₁₇ wherein m' is 1 or 2, --ZC(Z)R₈ or --(CR₁₀ R₂₀)_(n)NR₇ R₁₇. Preferably the aryl group is an optionally substituted phenyl.

Preferred substitutions for the R₁ or R₂ group when it is a 4-phenyl,4-naphth-1-yl or 5-naphth-2-yl moiety are one or two substituents eachindependently selected from halogen, --SR₅, --SOR₅, --OR₃₆, or --(CR₁₀R₂₀)_(n) NR₁₀ R₂₀, and for other positions of substitution on theserings preferred substitution is halogen, --S(O)_(m) R₈, --OR₈, --(CR₁₀R₂₀)_(n) NR₇ R₁₇, --(CR₁₀ R₂₀)_(n) NR₁₀ C(Z)R₈ and --NR₆ S(O)_(m) R₆.More preferred substituents for the 4-position in phenyl and naphth-1-yland on the 5-position in naphth-2-yl include halogen, especially fluoroand chloro, more especially fluoro, and --SR₅ and --S(O)R₅ wherein R₅ ispreferably a C₁₋₂ alkyl, more preferably methyl; of which fluoro isespecially preferred.

Preferred substituents for the 3-position in phenyl and naphth-1-ylinclude: halogen, especially chloro; --OR₈, especially C₁₋₄ alkoxy;amino; --NR₁₀ C(Z)R₈, especially --NHCO(C₁₋₁₀ alkyl); and --NR₁₀S(O)_(m) R₁₁, especially --NHSO₂ (C₁₋₁₀ alkyl). Preferably, the arylgroup is an unsubstituted or substituted phenyl moiety. More preferably,it is phenyl or phenyl substituted at the 4-position with fluoro and/orsubstituted at the 3-position with fluoro, chloro, C₁₋₄ alkoxy,methanesulfonamido or acetamido.

Suitably, R₃ is Q-(Y₁)_(t) wherein Q is an aryl or heteroaryl group;andt is an integer having a value of 1 to 3; Y₁ is independentlyselected from hydrogen, C₁₋₅ alkyl, halo-substituted C₁₋₅ alkyl,halogen, or --(CR₁₀ R₂₀)_(n) Y₂.

Suitably Y₂ is hydrogen, halogen, --OR₈, --NO₂, --S(O)_(m') R₁₁, --SR₈,--S(O)_(m') OR₈, --S(O)_(m) NRSR₉, --NRSR₉, --O(CR₁₀ R₂₀)_(n) NRSR₉,--C(O)R₈, --CO₂ R₈, --CO₂ (CR₁₀ R₂₀)_(m") CONR₈ R₉, --ZC(O)R₈, --CN,--C(Z)NR₈ R₉, --NR₁₀ C(Z)R₈, --C(Z)NR₈ OR₉, --NR₁₀ C(Z)NR₈ R₉, --NR₁₀S(O)_(m) R₁₁, --N(OR₂₁)C(Z)NR₈ R₉, --N(OR₂₁)C(Z)R₈, --C(═NOR₂₁)R₈,--NR₁₀ C(═NR₁₅)SR₁₁, --NR₁₀ C(═NR₁₅)NR₈ R₉, --NR₁₀ C(═CR₁₄ R₂₄)SR₁₁,--NR₁₀ C(═CR₁₄ R₂₄)NR₈ R₉, --NR₁₀ C(O)C(O)NR₈ R₉, --NR₁₀ C(O)C(O)OR₁₀,--C(═NR₁₃)NR₈ R₉, --C(═NOR₁₃)NR₈ R₉, --C(═NR₁₃)ZR₁₁, --OC(Z)NR₈ R₉,--NR₁₀ S(O)_(m) CF₃, --NR₁₀ C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadizaol-3-yl or4-(R₁₂)-5-(R₁₈ R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl.

Preferably Q is phenyl which is optionally substitued. Preferablesubstituents include--(CR₁₀ R₂₀)_(n) Y₂ with Y₂ as --S(O)_(m') R₁₁,--SR₈, halogen or --CO₂ R₈ ; n is preferably 0 or 1.

Suitably R₄ is hydrogen, NR₁₆ R₂₆, NR₁₀ C(Z)R₁₁, NR₁₀ C(Z)NR₁₆ R₂₆, NR₁₀C(═NR₁₉)NR₆ R₂₆, or NR₁₀ C(Z)OR₁₀. Preferably R₄ is hydrogen or NR₁₆R₂₆. Suitably R₁₆ and R₂₆ are independently hydrogen, or C₁₋₄ alkyl orR₁₆ and R₂₆ together with the nitrogen to which they are attached form aheterocyclic or heteroaryl ring of 5-7 members optionally conatining anadditional heteroatom selected from oxygen, sulfur or NR22. Theheterocyclic and heteraryl ring may also be addtionally substituted.

In all instances herein where there is an alkenyl or alkynyl moiety as asubstituent group, the unsaturated linkage, i.e., the vinylene oracetylene linkage is preferably not directly attached to the nitrogen,oxygen or sulfur moieties, for instance in C(Z)NR₈ OR₉, NR₁₀ C(Z)NR₈ R₉,or OR₈.

As used herein, "optionally substituted" unless specified, refers tosuch groups as halogen, hydroxyl, alkoxy, S(O)_(m) C₁₋₆ alkyl, amino, amono & di-substituted amino, such as an NR₇ R₁₇ group, C₁₋₆ alkyl, haloC₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl or arylalkyl wherein the aryl moietyis optionally substituted by halogen, hydroxyl, alkoxy, S(O)_(m) C₁₋₆alkyl, amino, a mono & di-substituted 15 amino, such as an NR₇ R₁₇group, C₁₋₆ alkyl, halo C₁₋₆ alkyl, or C₃₋₇ cycloalkyl.

In a preferred subgenus of compounds of formula (I), R₁ is 4-pyridyl,2-alkyl-4-pyridyl, 2-NR₁₀ R₂₀ -4-pyridyl, 4-pyrimidinyl,2-alkyl-4-pyrimidinyl, 2-NR₁₀ R₂₀ -4-pyrimidinyl, or 4-quinolyl; R₂ isan optionally substituted phenyl group. More preferably R₂ is phenyl orphenyl substituted by fluoro, chloro, C₁₋₄ alkoxy, S(O)_(m) C₁₋₄ alkyl,methanesulfonamido or acetamido; R₃ is phenyl or optionally substituedphenyl and R₄ is hydrogen or NR₁₆ R₂₆.

Suitable pharmaceutically acceptable salts are well known to thoseskilled in the art and include basic salts of inorganic and organicacids, such as hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methane sulphonic acid, ethane sulphonic acid, aceticacid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,phenylacetic acid and mandelic acid. In addition, pharmaceuticallyacceptable salts of compounds of formula (I) may also be formed with apharmaceutically acceptable cation, for instance, if a substituent Y₁ inR₃ comprises a carboxy group. Suitable pharmaceutically acceptablecations are well known to those skilled in the art and include alkaline,alkaline earth, ammonium and quarternary ammonium cations.

The following terms, as used herein, refer to:

"halo"--all halogens, that is chloro, fluoro, bromo and iodo;

"C₁₋₁₀ alkyl" or "alkyl"--both straight and branched chain radicals of 1to 10 carbon atoms, unless the chain length is otherwise limited,including, but not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like;

The term "cycloalkyl" is used herein to mean cyclic radicals, preferablyof 3 to 7 carbons, including but not limited to cyclopropyl,cyclopentyl, cyclohexyl, and the like.

The term "alkenyl" is used herein at all occurrences to mean straight orbranched chain radical of 2-10 carbon atoms, unless the chain length islimited thereto, including, but not limited to ethenyl, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

"aryl"--phenyl and naphthyl;

"heteroaryl" (on its own or in any combination, such as"heteroaryloxy")--a 5-10 membered aromatic ring system in which one ormore tings contain one or more heteroatoms selected from the groupconsisting of N, O or S, such as, but not limited, to pyrrole,thiophene, quinoline, isoquinoline, pytidine, pyrimidine, oxazole,thiazole, thiadiazole, triazole, imidazole, or benzimidazole;

"heterocyclic" (on its own or in any combination, such as"heterocyclylalkyl")--a saturated or wholly or partially unsaturated4-10 membered ring system in which one or more rings contain one or moreheteroatoms selected from the group consisting of N, O, or S; such as,but not limited to, pyrrolidine, piperidine, piperazine, morpholine,imidazolidine or pyrazolidine;

The term "aralkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is usedherein to mean C₁₋₄ alkyl as defined above unless otherwise indicated

"sulfinyl"--the oxide S(O) of the corresponding sulfide while the term"thio" refers to the sulfide.

The compounds of the present invention may contain one or moreasymmetric carbon atoms and may exist in racemic and optically activeforms. All of these compounds are included within the scope of thepresent invention.

Compounds of Formula (I) are pyrazole derivatives which may be readilyprepared using procedures well known to those of skill in the art andmay be prepared by analagous methods to those indicated herein below.##STR3##

While the illustration in Schemes I is for the preparation of aparticular compound of Formula (I) (i.e., Scheme I, R₁ =-pyridyl, R₂=4-fluorophenyl, R₃ =methylsulfinylphenyl and R₄ is amino or hydrogen),generalization of the synthesis to groups claimed as R₁, R₂, R₃ and R₄herein can be achieved by starting with the appropriate propanenitrile,preparation of which are disclosed in EP 0 531 901 A2 whose disclosureis incorporated by reference herein. Treatment of the propanenitrilewith the appropriate arylhydrzine affords 5-aminopyrazole 3 as outlinedby Smith, P. A. S. et al., J. Org. Chem., 1970, 35(7), 2215. Pyrazole 3can be converted to the corresponding sulphonamide, amide, urea,guanidine or urethane by using techniques well known to those of skillin the art by the appropriate acylating agents, such as sulfonylchlorides, acid chlorides, isocyanates, dicyanamides and chloroformates,respectively. 5-Aminopyrazole 3 can also be converted to the5-diazopyrazole 4 by treatment with NaNO₂ and aqueous HCl. Following theprocedure of Hodgson, H. H. et al., J. Chem. So. London, 1944, 8,treatment of 4 with Cu₂ O and HOAc/H₂ SO₄) affords pyrazole 5.

Suitable protecting groups for use in the present invention, are wellknown in the art and described in many references, for instance,Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience,New York, 1981.

Pharmaceutically acid addition salts of compounds of formula (I) may beobtained in known manner, for example by treatment thereof with anappropriate amount of acid in the presence of a suitable solvent.

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention.

SYNTHETIC EXAMPLES EXAMPLE 13-(4-Fluorophenyl)-1-(4-methylsulfinylphenyl)-4-(4-pyridyl)-5H-pyrazole

(a) 4-(Methylthio)phenylhydrazine hydrochloride--The title compound isprepared following the procedure of Demers, J. P. et al., Tet. Lett.,1987, 28 (42), 4933.

(b) 3-(4-Fluorophenyl)-3-oxo-2-(pyridin-4-yl)propanenitrile--The titlecompound is prepared following the procedure of Oku, T. et at., EP 0 531901 A2.

(c)5-Amino-3-(4-fluorophenyl)-1-(methylthiophenyl)-4-(4-pyridyl)pyrazole--Thetitle compound is prepared following the procedure of Smith, P. A. S. etal., J. Org. Chem., 1970, 35 (7), 2215 except using4-(methylthio)phenylhydrazine hydrochloide and3-(4-fluorophenyl)-3-oxo-2-(pyridin-4-yl)propanenitrile.

(d)5-Diazo-3-(4-fluorophenyl)-1-(methylthiophenyl)-4-(4-pyridyl)pyrazole--5-Amino-3-(4-fluorophenyl)-1-(methylthiophenyl)-4-(4-pyridyl)pyrazoleis dissolved in a suitable volume of water containing 2.5-3 equivalentsof HCl. The solution is cooled in ice and maintained at 0°-5° C. whilean aqueous soluton of NaNO₂ is added porionwise. The NaNO₂ is addeduntil, after 3-4 min, the solution gives a positive result with a moistpotassium iodide-starch paper test. The title compound is used withoutfurther purification.

(e)3-(4-Fluorophenyl)-1-(methylthiophenyl)-4-(4-pyridyl)-5H-pyrazole--Thetitle compound is prepared following the procedure of Hodgson, H. H. etal., J. Chem. Soc. London, 1944, 8 except using5-diazo-3-(4-fluorophenyl)-1-(methylthiophenyl)-4-(4-pyridyl)pyrazole.

(f)3-(4-Fluorophenyl)-1-(4-methylsulfinylphenyl)-4-(4-pyridyl)-5H-pyrazole--Asolution of3-(4-fluorophenyl)-1-(methylthiophenyl)-4-(4-pyridyl)-5H-pyrazole inglacial acetic acid is added to an aqueous solution of K₂ S₂ O₈. Thesolution is stirred at rt for 18 h. The mixture is then poured into H₂ Oand the pH is adjusted to neutral with cone. NH₄ OH. The solid which isformed is collected to afford the title compound.

METHODS OF TREATMENT

The compounds of Formula (I) or a pharmaceutically acceptable saltthereof can be used in the manufacture of a medicament for theprophylactic or therapeutic treatment of any disease state in a human,or other mammal, which is excacerbated or caused by excessive orunregulated cytokine production by such mammal's cell, such as, but notlimited to monocytes and/or macrophages.

Compounds of formula (I) are capable of inhibiting proinflammatorycytokines, such as IL-1, IL-6, IL-8 and TNF and are therefore of use intherapy. IL-1, IL-8 and TNF affect a wide variety of cells and tissuesand these cytokines, as well as other leukocyte-derived cytokines, areimportant and critical inflammatory mediators of a wide variety ofdisease states and conditions. The inhibition of these pro-inflammatorycytokines is of benefit in controlling, reducing and alleviating many ofthese disease states.

Accordingly, the present invention provides a method of treating acytokine-mediated disease which comprises administering an effectivecytokine-interfering amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In particular, compounds of formula (I) or a pharmaceutically acceptablesalt thereof are of use in the prophylaxis or therapy of any diseasestate in a human, or other mammal, which is exacerbated by or caused byexcessive or unregulated IL-1, IL-8 or TNF production by such mammal'scell, such as, but not limited to, monocytes and/or macrophages.

Accordingly, in another aspect, this invention relates to a method ofinhibiting the production of IL-1 in a mammal in need thereof whichcomprises administering to said mammal an effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, endotoxemia and/ortoxic shock syndrome, other acute or chronic inflammatory disease statessuch as the inflammatory reaction induced by endotoxin or inflammatorybowel disease, tuberculosis, atherosclerosis, muscle degeneration,multiple sclerosis, cachexia, bone resorption, psoriatic arthritis,Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis,rubella arthritis and acute synovitis. Recent evidence also links IL-1activity to diabetes, pancreatic β cells and Alzheimer's disease.

In a further aspect, this invention relates to a method of inhibitingthe production of TNF in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof.

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoisosis, bone resorption diseases, such asosteoporosis, reperfusion injury, graft vs. host reaction, allograftrejections, fever and myalgias due to infection, such as influenza,cachexia secondary to infection or malignancy, cachexia secondary toacquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS relatedcomplex), keloid formation, scar tissue formation, Crohn's disease,ulceralive coliris and pyresis.

Compounds of formula (I) are also useful in the treatment of viralinfections, where such viruses are sensitive to upregulation by TNF orwill elicit TNF production in vivo. The viruses contemplated fortreatment herein are those that produce TNF as a result of infection, orthose which are sensitive to inhibition, such as by decreasedreplication, directly or indirectly, by the TNF inhibiting-compounds offormula (1). Such viruses include, but are not limited to HIV-1, HIV-2and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpesgroup of viruses, such as but not limited to, Herpes Zoster and HerpesSimplex. Accordingly, in a further aspect, this invention relates to amethod of treating a mammal, preferably a human, afflicted with a humanimmunodeficiency virus (HIV) which comprises administering to suchmammal an effective TNF inhibiting amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof.

Compounds of formula (I) may also be used in association with theveterinary treatment of mammals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to, the lentivirusinfections such as equine infectious anaemia virus, caprine arthritisvirus, visna virus, or the maedi virus, or the retroviruses, such asfeline immunodeficiency virus (FIV), bovine immunodeficiency virus, orcanine immunodeficiency virus.

The compounds of formula (I) may also be used topically in the treatmentor prophylaxis of topical disease states mediated by or exacerbated byexcessive cytokine production, such as by IL-1 or TNF respectively, suchas inflamed joints, eczema, psoriasis and other inflammatory skinconditions such as sunburn; inflammatory eye conditions includingconjunctivitis; pyresis, pain and other conditions associated withinflammation.

Another aspect of the present invention relates to a method ofinhibiting the production of IL-8 (Interleukin-8, NAP) in a mammal inneed thereof which comprises administering to said mammal an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

There are many disease states in which excessive or unregulated IL-8production is implicated in exacerbating and/or causing the disease.These diseases are characterized by massive neutrophil infiltration suchas, psoriasis, inflammatory bowel disease, asthma, cardiac and renalreperfusion injury, adult respiratory distress syndrome, thrombosis andglomerulonephritis. All of these diseases are associated with increasedIL-8 production which is responsible for the chemotaxis of neutrophilsinto the inflammatory site. In contrast to other inflammatory cytokines(IL-1, TNF, and IL-6), IL-8 has the unique property of promotingneutrophil chemotaxis and activation. Therefore, the inhibition of IL-8production would lead to a direct reduction in the neutophilinfiltration.

The compounds of formula (I) are administered in an amount sufficient toinhibit cytokine, in particular IL-1, IL-8 or TNF, production such thatit is regulated down to normal levels, or in some case to subnormallevels, so as to ameliorate or prevent the disease state. Abnormallevels of IL-1, IL-8 or TNF, for instance in the context of the presentinvention, constitute: (i) levels of free (not cell bound) IL-1, IL-8 orTNF greater than or equal to 1 picogram per ml; (ii) any cell associatedIL-1, IL-8 or TNF; or (iii) the presence of IL-1, IL-8 or TNF mRNA abovebasal levels in cells or tissues in which IL-1, IL-8 or TNF,respectively, is produced.

The discovery that the compounds of formula (I) are inhibitors ofcytokines, specifically IL-1, IL-8 and TNF is based upon the effects ofthe compounds of formulas (I) on the production of the IL-1, IL-8 andTNF in in vitro assays which are described herein.

As used herein, the term "inhibiting the production of IL-1 (IL-8 orTNF)" refers to:

a) a decrease of excessive in vivo levels of the cytokine (IL-1, IL-8 orTNF) in a human to normal or sub-normal levels by inhibition of the invivo release of the cytokine by all cells, including but not limited tomonocytes or macrophages;

b) a down regulation, at the genomic level, of excessive in vivo levelsof the cytokine (IL-1, IL-8 or TNF) in a human to normal or sub-normallevels;

c) a down regulation, by inhibition of the direct synthesis of thecytokine (IL-1, IL-8 or TNF) as a postranslational event; or

d) a down regulation, at the translational level, of excessive in vivolevels of the cytokine (IL-1, IL-8 or TNF) in a human to normal orsub-normal levels.

As used herein, the term "TNF mediated disease or disease state" refersto any and all disease states in which TNF plays a role, either byproduction of TNF itself, or by TNF causing another monokine to bereleased, such as but not limited to IL-1, IL-6 or IL-8. A disease statein which, for instance, IL-1 is a major component, and whose productionor action, is exacerbated or secreted in response to TNF, wouldtherefore be considered a disease stated mediated by TNF.

As used herein, the term "cytokine" refers to any secreted polypeptidethat affects the functions of cells and is a molecule which modulatesinteractions between cells in the immune, inflammatory or hematopoieticresponse. A cytokine includes, but is not limited to, monokines andlymphokines, regardless of which cells produce them. For instance, amonokine is generally referred to as being produced and secreted by amononuclear cell, such as a macrophage and/or monocyte. Many other cellshowever also produce monokines, such as natural killer cells,fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epideral keratinocytes andB-lymphocytes. Lymphokines are generally referred to as being producedby lymphoctye cells. Examples of cytokines include, but are not limitedto, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8),Tumor Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor beta(TNF-β).

As used herein, the term "cytokine interfering" or "cytokine suppressiveamount" refers to an effective amount of a compound of formula (I) whichwill cause a decrease in the in vivo levels of the cytokine to normal orsub-normal levels, when given to a patient for the prophylaxis ortreatment of a disease state which is exacerbated by, or caused by,excessive or unregulated cytokine production.

As used herein, the cytokine referred to in the phrase "inhibition of acytokine, for use in the treatment of a HIV-infected human" is acytokine which is implicated in (a) the initiation and/or maintenance ofT cell activation and/or activated T cell-mediated HIV gene expressionand/or replication and/or (b) any cytokine-mediated disease associatedproblem such as cachexia or muscle degeneration.

As TNF-β (also known as lymphotoxin) has close structural homology withTNF-α (also known as cachectin) and since each induces similar biologicresponses and binds to the same cellular receptor, both TNF-α and TNF-βare inhibited by the compounds of the present invention and thus areherein referred to collectively as "TNF" unless specifically delineatedotherwise.

In order to use a compound of formula (I) or a pharmaceuticallyacceptable salt thereof in therapy, it will normally be formulated intoa pharmaceutical composition in accordance with standard pharmaceuticalpractice. This invention, therefore, also relates to a pharmaceuticalcomposition comprising an effective, non-toxic amount of a compound offormula (I) and a pharmaceutically acceptable carrier or diluent.

Compounds of formula (I), pharmaceutically acceptable salts thereof andpharmaceutical compositions incorporating such may conveniently beadministered by any of the routes conventionally used for drugadministration, for instance, orally, topically, parenterally or byinhalation. The compounds of formula (I) may be administered inconventional dosage forms prepared by combining a compound of formula(I) with standard pharmaceutical carriers according to conventionalprocedures. The compounds of formula (I) may also be administered inconventional dosages in combination with a known, second therapeuticallyactive compound. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation. It will be appreciated that the form and character of thepharmaceutically acceptable character or diluent is dictated by theamount of active ingredient with which it is to be combined, the routeof administration and other well-known variables. The carrier(s) must be"acceptable" in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly, the carrier or diluent may includetime delay material well known to the art, such as glycerylmono-stearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. When a liquid carrier is used,the preparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or nonaqueousliquid suspension.

Compounds of formula (I) may be administered topically, that is bynonsystemic administration. This includes the application of a compoundof formula (I) externally to the epidermis or the buccal cavity and theinstillation of such a compound into the ear, eye and nose, such thatthe compound does not significantly enter the blood stream. In contrast,systemic administration refers to oral, intravenous, intraperitoneal andintramuscular administration.

Formulations suitable for topical administration include liquid orsemiliquid preparations suitable for penetration through the skin to thesite of inflammation such as liniments, lotions, creams, ointments orpastes, and drops suitable for administration to the eye, ear or nose.The active ingredient may comprise, for topical administration, from0.001% to 10% w/w, for instance from 1% to 2% by weight of theformulation. It may however comprise as much as 10% w/w but preferablywill comprise less than 5% w/w, more preferably from 0.1% to 1% w/w ofthe formulation.

Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone,and/or a moisturizer such as glycerol or an oil such as castor oil orarachis oil.

Creams, ointments or pastes according to the present invention aresemi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy base. The base may comprise hydrocarbonssuch as hard, soft or liquid paraffin, glycerol, beeswax, a metallicsoap; a mucilage; an oil of natural origin such as almond, corn,arachis, castor or olive oil; wool fat or its derivatives or a fattyacid such as steric or oleic acid together with an alcohol such aspropylene glycol or a macrogel. The formulation may incorporate anysuitable surface active agent such as an anionic, cationic or non-ionicsurfactant such as a sorbitan esteror a polyoxyethylene derivativethereof. Suspending agents such as natural gums, cellulose derivativesor inorganic materials such as silicaceous silicas, and otheringredients such as lanolin, may also be included.

Drops according to the present invention may comprise sterile aqueous oroily solutions or suspensions and may be prepared by dissolving theactive ingredient in a suitable aqueous solution of a bactericidaland/or fungicidal agent and/or any other suitable preservative, andpreferably including a surface active agent. The resulting solution maythen be clarified by filtration, transferred to a suitable containerwhich is then sealed and sterilized by autoclaving or maintaining at98°-100° C. for half an hour. Alternatively, the solution may besterilized by filtration and transferred to the container by an aseptictechnique. Examples of bactericidal and fungicidal agents suitable forinclusion in the drops are phenylmercuric nitrate or acetate (0.002%),benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).Suitable solvents for the preparation of an oily solution includeglycerol, diluted alcohol and propylene glycol.

Compounds of formula (I) may be administered parenterally, that is byintravenous, intramuscular, subcutaneous intranasal, intrarectal,intravaginal or intraperitoneal administration. The subcutaneous andintramuscular forms of parenteral administration are generallypreferred. Appropriate dosage forms for such administration may beprepared by conventional techniques. Compounds of formula (I) may alsobe administered by inhalation, that is by intranasal and oral inhalationadministration. Appropriate dosage forms for such administration, suchas an aerosol formulation or a metered dose inhaler, may be prepared byconventional techniques.

For all methods of use disclosed herein for the compounds of formula(I), the daily oral dosage regimen will preferably be from about 0.1 toabout 80 mg/kg of total body weight, preferably from about 0.2 to 30mg/kg, more preferably from about 0.5 mg to 15 mg. The daily parenteraldosage regimen about 0.1 to about 80 mg/kg of total body weight,preferably from about 0.2 to about 30 mg/kg, and more preferably fromabout 0.5 mg to 15 mg/kg. The daily topical dosage regimen willpreferably be from 0.1 mg to 150 mg, administered one to four,preferably two or three times daily. The daily inhalation dosage regimenwill preferably be from about 0.01 mg/kg to about 1 mg/kg per day. Itwill also be recognized by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound of formula (I)or a pharmaceutically acceptable salt thereof will be determined by thenature and extent of the condition being treated, the form, route andsite of administration, and the particular patient being treated, andthat such optimums can be determined by conventional techniques. It willalso be appreciated by one of skill in the art that the optimal courseof treatment, i.e., the number of doses of a compound of formula (I) ora pharmaceutically acceptable salt thereof given per day for a definednumber of days, can be ascertained by those skilled in the art usingconventional course of treatment determination tests.

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention.

BIOLOGICAL EXAMPLES

The cytokine-inhibiting effects of compounds of the present inventionare determined by the following in vitro assays:

Interleukin 1 (IL-1)

Human peripheral blood monocytes are isolated and purified from eitherfresh blood preparations from volunteer donors, or from blood bank buffycoats, according to the procedure of Colotta et al, J Immunol, 132, 936(1984). These monocytes (1×10⁶) are plated in 24-well plates at aconcentration of 1-2 million/ml per well. The cells are allowed toadhere for 2 hours, after which time nonadherent cells are removed bygentle washing. Test compounds are then added to the cells for 1 hbefore the addition of lipopolysaccharide (50 ng/ml), and the culturesare incubated at 37° C. for an additional 24 h. At the end of thisperiod, culture super-natants are removed and clarified of cells and alldebris. Culture supernatants are then immediately assayed for IL-1biological activity, either by the method of Simon et al., J. Immunol.Methods, 84, 85, (1985) (based on ability of IL-1 to stimulate aInterleukin 2 producing cell line (EL-4) to secrete IL-2, in concertwith A23187 ionophore) or the method of Lee et al., J. ImmunoTherapy, 6(1), 1-12 (1990) (ELISA assay).

Tumor Necrosis Factor (TNF)

Human peripheral blood monocytes are isolated and purified from eitherblood bank buffy coats or plateletpheresis residues, according to theprocedure of Colotta, R. et al., J Immunol, 132(2), 936 (1984). Themonocytes are plated at a density of 1×10⁶ cells/ml medium/well in24-well multi-dishes. The cells are allowed to adhere for 1 hour afterwhich time the supernatant is aspirated and fresh medium (1 ml,RPMI-1640, Whitaker Biomedical Products, Whitaker, Calif.) containing 1%fetal calf serum plus penicillin and streptomycin (10 units/ml) added.The cells are incubated for 45 minutes in the presence or absence of atest compound at 1 nM-10 mM dose ranges (compounds were solubilized indimethyl sulfoxide/ethanol, such that the final solvent concentration inthe culture medium is 0.5% dimethyl sulfoxide/0.5% ethanol). Bacteriallipopoly-saccharide (E. coli 055:B5 [LPS] from Sigma Chemicals Co.) isthen added (100 ng/ml in 10 ml phosphate buffered saline) and culturesincubated for 16-18 hours at 37° C. in a 5% CO₂ incubator. At the end ofthe incubation period, culture supernatants are removed from the cells,centrifuged at 3000 rpm to remove cell debris. The supernatant is thenassayed for TNF activity using either a radio-immuno or an ELISA assay,as described in WO 92/10190 and by Becker et at., J Immunol, 1991, 147,4307.

Interleukin 8 (IL-8)

Primary human umbilical cord endothelial cells (HUVEC) (Cell Systems,Kirland, Wash.) are maintained in culture medium supplemented with 15%fetal bovine serum and 1% CS-HBGF consisting of aFGF and heparin. Thecells are then diluted 20-fold before being plated (250 μl) intogelating coated 96-well plates. Prior to use, culture medium is replacedwith fresh medium (200 μl). Buffer or test compound (25 μl, atconcentrations between 1 and 10 μM) is then added to each well inquadruplicate wells and the plates incubated for 6 h in a humidifiedincubator at 37° C. in an atmosphere of 5% CO₂. At the end of theincubation period, supernatant is removed and assayed for IL-8concentration using an IL-8 ELISA kit obtained from R&D Systems(Minneapolis, Minn.). All data is presented as mean value (ng/ml) ofmultiple samples based on the standard curve. IC₅₀ 's where appropriateare generated by non-linear regression analysis.

CSAID's (Cytokine Suppresive Anti-Inflammatory Drug) BindingAssay--Cytokine Specific Binding Protein

A radiocompetitive binding assay was developed to provide a highlyreproducible primary screen for structure-activity studies. This assayprovides many advantages over the conventional bioassays which utilizefreshly isolated human monocytes as a source of cytokines and ELISAassays to quantify them. Besides being a much more facile assay, thebinding assay has been extensively validated to highly correlate withthe results of the bioassay. A specific and reproducible CSAID bindingassay was developed using soluble cystosolic fraction from THP.1 cellsand a radiolabeled compound. For instance, a suitable radiolabeledcompound of the CSAID class is4-(Fluorophenyl)-2-(4-hydroxyphenyl-3,5-t₂)-5-(4-pyridyl)imidazole. Inbrief, the THP.1 cytosol was routinely prepared from cell lysateobtained by nitrogen cavitation followed by a 10 K×g low speed and a 100K×g high speed centrifugation, the supernatant of which was designatedas the cytosolic fraction. THP.1 cytosol was incubated withappropriately diluted radioligand at room temperature for apre-determined time to allow the binding to achieve equilibrium. Thesample was added to a G-10 column and eluted with 20 mm TRN, 50mMb--mercaptoethanol, NaN₃. The fraction encompassing the void volumewas collected and the radioactivity was assessed by liquid scintillationcounting. This was determined to reflect bound radioligand since theradioactive signal was abrogated by the presence of excess cold ligandin the incubation mixture or when there was no cytosolic fractionpresent. Compounds of Formula (I) at various doses are added to thebinding assay to achieve inhibition of binding of the radiolabel. IC₅₀ sas well as Ki values are determined by regression analysis and scatchardplot analysis respectively. There is generally excellent correlationbetween the IC₅₀ of compounds tested in both the binding assay and thebioassay and can be used interchangeably in many cases.

U.S. patent application Ser. No. 08/123,175 Lee et al., filed September1993 whose disclosure is incorporated by reference herein in itsentirety describes the above noted method for screening drugs toidentify compounds which interact with and bind to the CSBP. However,for purposes herein the binding protein may be in isolated form insolution, or in immobilized form, or may be genetically engineered to beexpressed on the surface of recombinant host cells such as in phagedisplay system or as fusion proteins. Alternatively, whole cells orcytosolic fractions comprising the CSBP may be employed in the creeningprotocol. Regardless of the form of the binding protein, a plurality ofcompounds are contacted with the binding protein under conditionssufficient to form a compound/binding protein complex and compoundcapable of forming, enhancing or interfering with said complexes aredetected.

More specifically, the CSAID Binding Assay is performed as follows:

MATERIALS:

Incubation buffer: 20 mM Tris, 1 mM MgCl₂, 20 mM Hepes, 0.02% NaN₃,store at 4° C. Elution buffer: 20 mM Tris, 50 mM 2-mercaptoethanol,NaN₃, store at 4° C.

G-10 Sephadex: add 100 g Sephadex G-10 (Pharmacia, Uppsala, Sweden) to400 mL dd H₂ O and allow to swell at room temperature for 2 hours.Decant fines and wash 3 times. Add NaN₃ and qs with dd H₂ O to 500 mLsand store at 4° C.

Assemble Columns: Straw column, filter frit and tip (Kontes, SP420160-000, 420162-002). Lowsorb tubes (Nunc) used in binding reaction.THP.1 cytosol spun at 15000 rpm for 5 min to clarify. THP.1 cytosolprepared by hypnotic treatment of cells and lysis by decompression innitrogen. Nuclei and membrane fragments removed by differentialcentrifugation (10,000 g for 1 hour and 100,000 g for 1 hour).

Compounds: Non-radioactive Compound I with corresponding EtOH control(dilutions made in incubation buffer) and ³ H-Compound I (dilutions inincubation buffer)

METHOD:

A. Column Preparation

1. Begin 30 min before anticipated elution of reaction mixture.

2. Add 3 mL of G-10 slurry to column for bed vol of 1.5 ml.

3. Rinse with 7 mL elution buffer (fill to top of column)

4. Cut columns down to size.

B. Sample Incubation

1. 15 min incubation at 4° C.

2. Binding reaction mixture; 100 μL cytosol, 10 μL cold Compound I orEtOH control, 10 μL ³ H-Compound I (molar concentration depends onnature of study).

3. "Free" control=100 μL incubation buffer in lieu of cytosolpreparation.

C. Sample Elution

1. Elute at 4° C.

2. Add total reaction volume to G-10 column.

3. Add 400 μL elution buffer to column and discard eluate.

4. Add 500 μL elution buffer to column, collecting eluted volume in 20ml scintillation vial.

5. Add 15 mL Ready Safe scintillation fluid.

6. Vortex and count in liquid scintillation counter for 5 minutes.Include a "total input counts control" (10 μL of labeled ligand).

D. Data Analysis

1. Plot DPMS as ouptut in graphic form and analyze by regressionanalysis and "Lundon ligand binding" software for the determination ofIC 50 and Kd/Ki respectively.

2. Rank order the IC50s of the tested compounds in the CSAIDbioassay andcompare to that generated by the CSAID binding assay and establish acorrelation curve.

The binding assay was further validated by the following criteria:

THP.1 cytosol demonstrated saturable and specific binding of theradiolabeled compound.

Preparation of4-(Fluorophenyl)-2-(4-hydroxyphenyl-3,5-t₂)-5-(4pyridyl)imidazole,(Compound I).

A 2.9 mg (0.0059 mmol) portion of2-(3,5-Dibromo-4-hydroxyphenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole,Compound I(p), was dissolved in 0.95 mL of dry DMF and 0.05 mL oftriethylamine in a 2.4 mL round bottom flask equipped with a smallmagnetic stirring bar. A 1.7 mg portion of 5% Pd/C (Engelhard lot 28845)was added, and the flask was attached to the stainless steel tritiummanifold. The mixture was degassed through four freeze-pump-thaw cycles,then tritium gas (5.3 Ci, 0.091 mmol) was introduced. The reactionmixture was allowed to warm to room temperature and was stirredvigorously for 20 h. The mixture was frozen in liquid nitrogen, theremaining tritium gas (2.4 Ci) was removed, and the flask was removedfrom the manifold. The reaction mixture was transferred, using 3×1 mL ofmethanol as rinsings, into a 10 mL round bottom flask, and the solventswere removed by static vacuum transfer. A 1.5 mL portion of methanol wasadded to the residue, then removed by static vacuum transfer. The latterprocess was repeated. Finally, the residue was suspended in 1.5 mL ofethanol and filtered through a syringe-tip Millipore filter (0.45micron), along with 3×ca. 1 mL ethanol rinsings. The total filtratevolume was determined to be 3.9 mL, and the total radioactivity, 94.2mCi. Solution was determined to be 3.9 mL, and the total radioactivity,94.2 mCi. HPLC analysis of filtrate (Partisil 5 ODS-3, 4.6 mm I.D.×25cm, 1 mL/min of 70:30:01 water/acetonitrile/trifluoroacetic acid,Radiomatic Flo-One Beta radio detector with 3 mL/min of Ecoscint-Hcocktail through a 0.75 mL cell) showed the presence of Compound I(R_(t) =60 min. ca. 37% of total radioactivity), and a discreteintermediate presumed to be the monobromo derivative Compound Ia (R_(t)=11.8 min, ca. 9% ).

The filtrate solution was evaporated to near dryness with a stream ofnitrogen, and the residue was dissolved in about 1.2 mL of the HPLCmobile phase. The solution was separated by HPLC as shown below, and thepeaks corresponding to Compounds I and Ia are collected separately.

    ______________________________________                                        HPLC Method                                                                   ______________________________________                                        Column        Altex Ultrasphere                                                             10 mm I.D. × 25 cm                                        Mobile Phase  70:30:0.1                                                                     water/acetonitrile/trifluoroacetic acid                         Flow Rate     5 mL/min                                                        UV detection  210 nm                                                          Injection Volumes                                                                           0.05-0.4 m:                                                     Retention Times                                                                             7.8 min Compound I                                                            24 min Compound Ia                                              ______________________________________                                    

The pooled Compound I fractions totaled 32 mL in volume and theradioactive concentration was 1.52 mCi/mL (total 48.6 m Ci). The pooledSB Compound Ia [³ H] fractions (totaling 10.1 mCi) were evaporated todryness and the residue was transferred quantitatively into a glass vialusing 3.8 mL of absolute ethanol for further analysis.

An 8 mL (12.2 mCi) portion of Compound I was evaporated to dryness invacuo at <35° C., then redissolved in 0.5 mL of mobile phase. The wholevolume was injected into the HPLC system described above, and theappropriate peak was collected. Evaporation of the collected eluate invacuo at <35° C. and transfer of the yellow residue into a vial withabsolute ethanol provided a solution (3.8 mL, 2.44 mCi/mL) of CompoundI. The portion of this solution used for NMR analyses was firstevaporated to dryness using stream of nitrogen then taken up in CD₃ OD.

Analysis of4-(4-Fluorophenyl)-2-(4-hydroxyphenyl-3,5-t₂)-5-(4-pyridyl)imidazole,Compound I.

    ______________________________________                                        Radiochemical Purity by HPLC                                                  Method                                                                        Column      Ultrasphere Octyl, 5 mm, 4.6 mm                                               I.D. × 25 cm, Beckman                                       Mobile Phase                                                                              350:150:0.5 (v/v/v)                                                           water/acetonitrile/trifluoroacetic acid                           Flow Rate   1.0 mL/min                                                        Mass detection                                                                            UV at 210 nm                                                      Radioactivity                                                                             Ramona-D radioactivity flow detector                              detection                                                                     Scintillator                                                                              Tru-Count (Tru-Lab Supply Co.)                                    Flow rate   5.0 mL/min                                                        Cell volume 0.75 mL                                                           Retention time                                                                            7.7 min                                                           Result      98.7                                                              Radioactive Concentration by Scintillation Counting                           Method                                                                        Scintillator                                                                              Ready Safe (Beckman Instruments, Inc.)                            Instrument  TM Analytic model 6881                                            Efficiency  Automated DPM calculation from quench                                         curve                                                             Result      2.44 mCi/mL                                                       Specific Activity by Mass Spectrometry                                        Method      CI-MS, NH.sub.3 reagent gas                                       Result      20.0 Ci/mmol                                                                  .sup.3 H Distribution:                                                      Unlabeled 44%                                                                 Single Label                                                                            43%                                                                 Double Label                                                                            13%                                                       .sup.3 H NMR.sup.9                                                            Method                                                                        Instrument  Brunker AM 400                                                    Experiment  Proton decoupled .sup.3 H NMR                                                 Proton non-decoupled .sup.3 H NMR                                             Proton non-decoupled .sup.3 H NMR                                 Peak Referencing                                                                          Solvent Peak of methanol ∂ 3.3                       Solvent     Methanol-d.sub.4                                                  Result      Tritium is incorporated exclusively on the                                    carbon atoms ortho to aromatic hydroxyl                                       group                                                             ______________________________________                                        Analytical Summary                                                            Assay                  Result                                                 ______________________________________                                        Radiochemical purity determined by HPLC                                                              98.7%                                                  Radioactivity concentration determined by                                                            2.44 mCi/mL                                            scintillation counting                                                        Specific activity determined by mass                                                                 20.0 Ci/mmol                                           spectrometry .sup.3 H NMR                                                                            agrees with the                                                               proposed structure                                     ______________________________________                                    

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore the Examples herein are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

What is claimed is:
 1. A compound of the formula: ##STR4## wherein oneof R₁ and R₂ is a 4-pyridyl ring, which ring is optionally substitutedwith one or two substituents each of which is independently selectedfrom C₁₋₄ alkyl, halo, C₁₋₄ alkoxy, C₁₋₄ alkylthio, CH₂ OR₈, NH₂, mono-or di-C₁₋₆ -alkylamino or N-heterocyclyl ring selected from pyrrolidine,piperidine, piperazine, morpholine, imidazolidine, and pyrazolidine;theother of R₁ and R₂ is selected from an optionally substituted phenylring, or naphthyl ring, which ring is substituted by one or twosubstituents, each of which is independently selected, and which, for a4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl substituent, is halo, nitro,cyano, --C(Z)NR₇ R₁₇, --C(Z)OR₂₃, --(CR₁₀ R₂₀)_(n) COR₃₆, --SR₅,--S(O)R₅, --OR₃₆, halo-substituted C₁₋₄ alkyl, C₁₋₄ alkyl, --ZC(Z)R₃₆,--NR₁₀ C(Z)R₂₃, or --(CR₁₀ R₂₀)_(n) NR₁₀ R₂₀ and which, for otherpositions of substitution, is halo, --(CR₁₀ R₂₀)_(n) nitro, --(CR₁₀R₂₀)_(n) cyano, --(CR₁₀ R₂₀)_(n) C(Z)NR₁₆ R₂₆, --(CR₁₀ R₂₀)_(n)C(Z)OR₁₈, --(CR₁₀ R₂₀)_(n) COR₂₅, --(CR₁₀ R₂₀)_(n) -S(O)_(m) R₈, --(CR₁₀R₂₀)_(n) OH, --(CR₁₀ R₂₀)_(n) OR₂₅, halo-substituted-C₁₋₄ alkyl, --C₁₋₄alkyl, --(CR₁₀ R₂₀)_(n) NR₁₀ C(Z)R₂₅, --(CR₁₀ R₂₀)_(n) NHS(O)_(m) R₆,--(CR₁₀ R₂₀)_(n) NHS(O)_(m) NR₇ R₁₇, --(CR₁₀ R₂₀)_(n) NR₆ S(O)_(m) R₆,--(CR₁₀ R₂₀)_(n) NR₆ S(O)_(m') NR₇ R₁₇ ; --(CR₁₀ R₂₀)_(n) ZC(Z)R₁₈ or--(CR₁₀ R₂₀)_(n) NR₇ R₁₇ ; n is 0 or an integer of 1 or 2; m is 0 or aninteger of 1 or 2; m' is an integer of 1 or 2; R₃ is Q-(Y₁)_(t) ; Q isan aryl; t is an integer having a value of 1 to 3; R₄ is hydrogen, C₁₋₁₀alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl, C₅₋₇cycloalkenyl-C₁₋₁₀ aryl, arylC₁₋₁₀ alkyl, --(CR₁₀ R₂₀)_(n') OR₁₂, (CR₁₀R₂₀)_(n) OR₁₃, (CR₁₀ R₂₀)_(n) S(O)_(m) R₁₈, (CR₁₀ R₂₀)_(n) NHS(O)₂ R₁₈,(CR₁₀ R₂₀)_(n) NR₁₆ R₂₆, (CR₁₀ R₂₀)_(n) NO₂, (CR₁₀ R₂₀)_(n) CN, (CR₁₀R₂₀)_(n') SO₂ R₁₈, (CR₁₀ R₂₀)_(n) S(O)_(m') NR₁₆ R₂₆, (CR₁₀ R₂₀)_(n)C(Z)R₁₃, (CR₁₀ R₂₀)_(n) OC(Z)R₁₃, (CR₁₀ R₂₀)_(n) C(Z)OR₁₃, (CR₁₀R₂₀)_(n) C(Z)NR₁₆ R₂₆, (CR₁₀ R₂₀)_(n) C(Z)NR₁₃ OR₉, (CR₁₀ R₂₀)_(n) NR₁₀C(Z)R₁₁, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)NR₁₆ R₂₆, (CR₁₀ R₂₀)_(n) N(OR₆)C(Z)NR₁₆R₂₆, (CR₁₀ R₂₀)_(n) N(OR₆)C(Z)R₁₃, (CR₁₀ R₂₀)_(n) C(═NOR₆)R₁₃, (CR₁₀R₂₀)_(n) NR₁₀ C(═NR₁₉)NR₁₆ R₂₆, (CR₁₀ R₂₀)_(n) OC(Z)NR₁₆ R₂₆, (CR₁₀R₂₀)_(n) NR₁₀ C(Z)NR₁₆ R₂₆, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)OR₁₀, wherein thearyl, cycloalkyl, cycloalkylalkyl can be optionally substituted byhalogen, hydroxyl, C₁₋₆ alkoxy, S(O)m C₁₋₆ alkyl, NR₇ R₁₇, C₁₋₆ alkyl,haloC₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, or aryalkyl; R₆ is C₁₋₁₀ alkyl,C₃₋₇ cycloalkyl, aryl, arylC₁₋₁₀ alkyl; R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl or NR₇ R₁₇, excluding the moieties --SR₅ being--SNR₇ R₁₇ and --SOR₅ being --SOH; R₁₆ and R₂₆ are independentlyhydrogen, or C₁₋₄ alkyl or R₁₆ and R₂₆ together with the nitrogen towhich they are attached form a heterocyclic selected from pyrrolidine,piperidine, piperazine, morpholine, imidazolidine, and pyrazolidine; Y₁is independently selected from hydrogen, C₁₋₅ alkyl, halo-substitutedC₁₋₅ alkyl, halogen, or --(CR₁₀ R₂₀)_(n) Y₂ ; Y₂ is hydrogen, halogen,--OR₈, --NO₂, --S(O)_(m') R₁₁, --SR₈, --S(O)_(m') OR₈, --S(O)_(m) NR₈R₉, --NR₈ R₉, --O(CR₁₀ R₂₀)_(n') NR₈ R₉, --C(O)R₈, --CO₂ R₈, --CO₂ (CR₁₀R₂₀)_(m") CONR₈ R₉, --ZC(O)R₈, --CN, --C(Z)NR₈ R₉, --NR₁₀ C(Z)R₈,--C(Z)NR₈ OR₉, --NR₁₀ C(Z)NR₈ R₉, --NR₁₀ S(O)_(m') R₁₁, --N(OR₂₁)C(Z)NR₈R₉, --N(OR₂₁)C(Z)R₈, --C(═NOR₂₁)R₈, --NR₁₀ C(═NR₁₅)SR₁₁, --NR₁₀C(═NR₁₅)NR₈ R₉, --NR₁₀ C(═CR₁₄ R₂₄)SR₁₁, --NR₁₀ C(═CR₁₄ R₂₄)NR₈ R₉,--NR₁₀ C(O)C(O)NR₈ R₉, --NR₁₀ C(O)C(O)OR₁₀, --C(═NR₁₃)NR₈ R₉,--C(═NOR₁₃)NR₈ R₉, --C(═NR₁₃)ZR₁₁, --OC(Z)NR₈ R₉, --NR₁₀ S(O)_(m) CF₃,--NR₁₀ C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadizaol-3-yl or 4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; n' is 0 or an integer having avalue of 1 to 10; m" is an integer having a value of 1 to 10: R₇ and R₁₇is each independently selected from hydrogen or C₁₋₄ alkyl or R₇ and R₁₇together with the nitrogen to which they are attached form aheterocyclic ring selected from pyrrolidine, piperidine, piperazine,morpholine, imidazolidine, and pyrazolidine: R₈ is hydrogen, C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₁₀ alkyl; R₉ is hydrogen, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl,aryl, arylalkyl, or R₈ and R₉ may together with the nitrogen to whichthey are attached form a heterocyclic selected from pyrrolidine,piperidine, piperazine, morpholine, imidazolidine, and pyrazolidine; R₁₀and R₂₀ is each independently selected from hydrogen or C₁₋₄ alkyl; R₁₁is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, aryl C₁₋₁₀ alkyl; R₁₂is hydrogen, --C(Z)R₁₃, optionally substituted C₁₋₄ alkyl, optionallysubstituted aryl, optionally substituted aryl-C₁₋₄ alkyl, or S(O)₂ R₁₈ ;R₁₃ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₁₀ alkyl;R₁₄ and R₂₄ is each independently selected from hydrogen, alkyl, nitroor cyano; R₁₅ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl;R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₁₀ alkyl; R₁₉ ishydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl; R₂₁ is hydrogen, apharmaceutically acceptable cation, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, aryl,aryl C₁₋₄ alkyl, aroyl, or C₁₋₁₀ alkanoyl; R₂₂ is R₁₀ or C(Z)-C₁₋₄alkyl; R₂₃ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇cycloalkyl; R₂₅ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl,arylC₁₋₁₀ alkyl, (CR₁₀ R₂₀)_(n) OR₈, (CR₁₀ R₂₀)_(n) S(O)_(m) R₁₈, (CR₁₀R₂₀)_(n) NHS(O)₂ R₁₈, (CR₁₀ R₂₀)_(n) NR₇ R₁₇ ; wherein the aryl, orarylalkyl, is optionally substituted by halogen, hydroxyl, C₁₋₆ alkoxy,S(O)m C₁₋₆ alkyl, NR₇ R₁₇, C₁₋₆ alkyl, haloC₁₋₆ alkyl, C₃₋₇ cycloalkyl,aryl, or aryalkyl; R₃₆ is hydrogen or R₂₃ ; Z is oxygen: Aryl is phenylor naphthyl: or a pharmaceutically acceptable salt thereof.
 2. Thecompound according to claim 1 wherein the optional substituent is C₁₋₄alkyl or NR₁₀ R₂₀.
 3. The compound according to claim 1 wherein R₂ is anoptionally substituted phenyl.
 4. The compound according to claim 3wherein one or more optionally substituted are independently selectedfrom halogen, SR₅ or S(O)R₅ or methoxy.
 5. The compound according toclaim 1 wherein R₄ is hydrogen, NR₁₆ R₂₆, NR₁₀ C(Z)R₁₁, NR₁₀ C(Z)NR₁₆R₂₆, NR(₁₀)C(═NR₁₉)NR₁₆ R₂₆ or NR₁₀ C(Z)OR₁₀.
 6. The compound accordingto claim 5 wherein R₁₆ and R₂₆ are hydrogen or C₁₋₄ alkyl.
 7. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier or diluent and a compound according to claim
 1. 8. The compoundaccording to claim 1 wherein the 4-pyridyl is substituted by C₁₋₄ alkylor NR₁₀ R₂₀.
 9. The compound according to claim 4 wherein thesubstituent is fluoro, further substituted in the 4-position of thephenyl ring.
 10. The compound according to claim 5 wherein R₄ ishydrogen or NR₁₆ R₂₆.
 11. The compound according to claim 10 wherein R₄is NR₁₆ R₂₆ and R₁₆ R₂₆ together with the nitrogen to which they areattached form a heterocyclic selected from pyrrolidine, piperidine,piperazine, morpholine, imidazolidine, and pyrazolidine.
 12. Thecompound according to claim 1 wherein Q is phenyl.
 13. The compoundaccording to claim 12 wherein the phenyl is substituted by --(CR₁₀R₂₀)_(n) Y₂.
 14. The compound according to claim 13 wherein Y₂ is--S(O)_(m') R₁₁, --SR₈, halogen, or --CO₂ R₈.
 15. The compound accordingto claim 1 which is3-(4-Fluorophenyl)-1-(4-methylsulfinylphenyl)-4-(4-pyridyl)-5H-pyrazole;or 3-(4-Fluorophenyl)-1-(4-methylthiophenyl)-4-(4-pyridyl)-5H-pyrazole;or a pharmaceutically acceptable salt thereof.
 16. A method of treatingarthritis, or other arthritic conditions, in a mammal in need thereofwhich method comprises administering to said mammal an effective amountof a compound according to claim 1.